Defining the therapeutic selective dependencies for distinct subtypes of PI3K pathway-altered prostate cancers
| Autor: | Hsuan-An Chen, Samuel Haywood, Ninghui Mao, Neal Rosen, Zeda Zhang, Brett S. Carver, Charles L. Sawyers, Dan Li, Qing Chang, Andrew C. Hsieh, Elisa de Stanchina, Xiaoping Chen, Danielle Choi, Yu Chen, Young Sun Lee, Cindy Lee, Aura Agudelo Rivera, Guotai Xu |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Science General Physics and Astronomy Context (language use) P110α Models Biological General Biochemistry Genetics and Molecular Biology Article Receptor IGF Type 1 Mice Phosphatidylinositol 3-Kinases Targeted therapies Downregulation and upregulation Cell Line Tumor PTEN Animals Humans Phosphorylation Protein kinase B Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Insulin-like growth factor 1 receptor Feedback Physiological Multidisciplinary Prostate cancer biology PTEN Phosphohydrolase Prostatic Neoplasms food and beverages General Chemistry Up-Regulation Isoenzymes Organoids Cancer research biology.protein Signal transduction Signal Transduction |
| Zdroj: | Nature Communications, Vol 12, Iss 1, Pp 1-13 (2021) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | Previous studies have suggested that PTEN loss is associated with p110β signaling dependency, leading to the clinical development of p110β-selective inhibitors. Here we use a panel pre-clinical models to reveal that PI3K isoform dependency is not governed by loss of PTEN and is impacted by feedback inhibition and concurrent PIK3CA/PIK3CB alterations. Furthermore, while pan-PI3K inhibition in PTEN-deficient tumors is efficacious, upregulation of Insulin Like Growth Factor 1 Receptor (IGF1R) promotes resistance. Importantly, we show that this resistance can be overcome through targeting AKT and we find that AKT inhibitors are superior to pan-PI3K inhibition in the context of PTEN loss. However, in the presence of wild-type PTEN and PIK3CA-activating mutations, p110α-dependent signaling is dominant and selectively inhibiting p110α is therapeutically superior to AKT inhibition. These discoveries reveal a more nuanced understanding of PI3K isoform dependency and unveil novel strategies to selectively target PI3K signaling nodes in a context-specific manner. Understanding the mechanisms driving PI3K isoform dependency in prostate cancer can help the design of future clinical trials. Here, the authors show that gain-of-function mutations in PIK3CA or PIK3CB can confer PI3K p110 isoform dependency and that the direct inhibition of AKT may be superior to PI3K inhibition in PTEN-deficient prostate cancers. |
| Databáze: | OpenAIRE |
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